In this review by Sato et al, the authors outline translational research on molecular targets in the field of antiangiogenic and antivascular treatment. Given the recent clinical successes seen with such treatment, we have a wealth of new therapies on the horizon and it is helpful to see those novel and complicated treatments outlined in an organized manner.
The authors have chosen to separate antiangiogenic therapy and antivascular therapy. While this is quite helpful in a structured discussion of targets, it is important to realize that the major success stories thus far in clinical practice have involved agents with potential effects on both angiogenesis and established blood vessels as well as direct interaction with tumor cell receptors. As stated in their abstract, the authors have attempted to focus their discussion around targets with agents available in current clinical trials. In addition, they mention some of their own exciting preclinical data affecting targets such as integrins and matrix metalloproteinases, which have not yet translated into clinical trials. Although these targetable receptors or ligands are scientifically valid and may show preclinical signals of success, the majority are either in early-stage development or have led to disappointments in the clinic, as the authors note.
Since it is unknown what the future has in store for these agents and targets, we have attempted to put these bench-to-bedside novel therapeutics in the clinical context of late-stage and approved agents. In addition, we choose to highlight our own work with anti–prostate-specific membrane antigen (PSMA) antibodies as an example of bench-to-bedside work in antivascular therapy.
Recent Clinical Successes: Lessons Learned With School Still in Session
In recent years, several phase III clinical trials have demonstrated the utility of antiangiogenic treatment. In particular, bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), has been shown to be effective in combination with cytotoxic chemotherapy in metastatic colorectal, lung, and breast cancer. In addition, orally administered multitargeted tyrosine kinase inhibitors given as single agents (namely sunitinib [Sutent] and sorafenib [Nexavar]), have been shown to be effective in metastatic renal cell carcinoma, gastrointestinal stromal tumors, and hepatocellular carcinoma. Along with several phase I and II studies, these trials have definitively established that antiangiogenic therapies can be an additional tool in our treatment of advanced cancer.
These early and clear successes have paved the road for further novel antiangiogenic therapies, as outlined in this review. As we advance our understanding of tumor angiogenesis, our treatments will evolve as well. However, as new treatments are added to our therapeutic armamentarium, significant unanswered questions remain.
While it is difficult to argue with the clinical success of recent trials, they have not come without significant side effects. The addition of bevacizumab to cytotoxic chemotherapy seems to increase the incidence of arterial thromboembolic events. In addition, preliminary evidence of severe hemorrhagic toxicities has led to caution regarding use of these agents in subsets of patients or histologies. New toxicities such as hypertension and proteinuria have emerged. Some toxicities may be due to increased cytotoxic drug delivery, others due to class effects of antiangiogenic therapy, and others due to "off-target" effects.
Additional work needs to be done with the currently available antivascular treatments to potentially improve their efficacy and minimize their toxicity. Antiangiogenic treatment targets cancer in an untraditional way, attacking tumor vasculature rather than tumor cells themselves. Some target ligands of important receptors rather than individual tumor cells or their vasculature. Optimal dosing and schedules of administration remain to be defined. The traditional phase I dose-escalation trials aimed at defining a maximal tolerated dose to use in phase II trials may not be the best approach. In the era of "targeted" therapy, biologic or physiologic endpoints may be more important in defining the optimal regimens. Traditional assessments such as response rates calculated via decreases in sums of uni- or bidimensionally measured tumors on radiographs may not be as important as survival and quality-of-life outcomes. In addition, an optimal dose and schedule in one tumor type or host may be suboptimal in others.
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